Glutamate is the most abundant excitatory amino acids in the central nervous system (CNS). Glutamate acts through a number of receptors that affect both fast and slow neurotransmission. The fast ionotropic N-methyl-D-aspartate (NMDA), the amino-3-hydroxy-5-methyl-4-isoxazole (AMPA), and the slow metabotropic kainate receptor are a series of G-protein coupled receptors. The ionotropic NMDA receptors are excitatory which has binding sites for glutamate and glycine, and possess an important role in memory and in mood disorders. The metabotropic kainate glutamate receptors (mGluRs) are present at both presynaptic and postsynaptic sites and are considered major targets in the area of neuropharmacology, including schizophrenia, depression, learning, memory, anxiety, seizures, addiction to drugs, neurodegeneration and developmental regulation of synaptic circuits.
The anti-psychotic drugs are widely used in the treatment of central nervous system (CNS) psychotic diseases and disorders, such as schizophrenia. These agents block generally dopamine receptors and are divided into typical and atypical classes; phenothiazines are, for example, typical antipsychotics and clozapine, olanzapine and risperidone are classified as atypical antipsychotics. It is well known in the art that typical neuroleptic agents induce extrapyramidal symptoms, which include rigidity, tremor, bradykinesia (slow movement), and bradyphrenia (slow thought), as well as tardive dyskinesia, acute dystonic reactions and akathasia. Atypical antipsychotics cause minimal extrapyramidal symptoms and thus rarely cause tardive dyskinesias, akathasia or acute dystonic reactions. The administration of atypical antipsychotic agents involves other side effects such as increase of body weight, mood disturbances, sexual disfunction, sedation, orthostatic hypotension, hypersalivation, lowered seizure threshold and, in particular, agranulocytosis.
Schizophrenia is a chronic, debilitating disease with significant morbidity and mortality that often requires antipsychotic pharmacotherapy for life. Current therapy consists of neuroleptics of the typical and the atypical type which share a common anti-dopaminergic activity. In recent years, evidence has been accumulated suggesting that schizophrenia and bipolar disorders are also associated with disturbance in GABA and glutamate transmission in the brain. Recent studies suggest that schizophrenia is associated with NMDA receptor pathology. This hypothesis is based on the experimental finding that agents that block NMDA receptors such as phencyclidine (PCP) and MK-801 induce psychoses similar to that associated with schizophrenia. Post-mortem data in brains of schizophrenic patients showed also a decrease in the expression of several glutamate receptor subtypes including NMDA, AMPA and Kainate in different brain areas. Since hypo function of the NMDA system is considered to have an important role in schizophrenia, and schizophreniform psychosis caused by PCP resembles schizophrenia especially in negative symptoms and cognitive dysfunction, it was suggested that NMDA inhibition would lead to diminished GABAergic tone, which in turn will induce disinhibition of glutamatergic AMPA receptor resulting in excitotoxic neuronal damage and psychosis.
Since direct-acting NMDA agonists, such as glutamate, might be neurotoxic, research focused on assessing the therapeutic activity of partial or full agonists on the glycine (GLY) site of the NMDA receptors. Agents like D-serine and D-cycloserine (DCS) showed in some clinical studies an improvement of mainly primary negative symptoms of schizophrenia when used as adjuvants to conventional neuroleptics such as risperidone and olanzapine. Sarcosine is a glycine transporter 1 inhibitor found efficacious in improving symptoms (negative and positive) of patients with stable chronic schizophrenia. The disadvantage, however, associated in the use of these amino acids lies in the fact that they scarcely penetrate the blood brain barrier (BBB).
Glutamate receptors subtype antagonists, agonists and partial agonists are target of intensive research. The NMDA receptor antagonist memantine was developed for the treatment of Alzheimer's disease. The partial agonist agent D-cycloserine was found to induce some antidepressant and anxiolytic activity in animal models and to improve mood, insomnia and appetite. It is suggested that its anxiolytic effect is related to increased learning and fear extinction. Yet, a significant antidepressant activity of D-cycloserine compared to placebo in men was not observed. Furthermore, agents targeting both the ionotrophic and the metabotrophic receptors of glutamate are under different stages of development for the treatment of anxiety, depression, cognitive and motor disorders.